HFE (High Iron Fe) gene encodes the human hemochromatosis protein (HFE protein) which regulates iron homeostasis and can cause the iron overload disorder hereditary hemochromatosis. The HFE gene is located on short arm of chromosome 6 at location 6p21.3. Because iron is required during cell proliferation, excess of iron has been implicated in cancer development (Stevens et al., 1994; Dorak et al., 2005). C282Y (rs1800562) is a single nucleotide polymorphism (SNP) present in the HFE gene and represents the most common genetic mutation of the HFE gene.
Single nucleotide polymorphism (SNP) may influence gene functions and modifies an individual's susceptibility to diseases, such as cancers. In some instances, a single SNP may be sufficient to confer susceptibility, while in others multiple SNPs may act jointly to influence disease susceptibility. There are at least five (5) SNPs that are present within the HFE gene. C282Y (rs180052) in the HFE gene was first reported to be a risk marker for childhood acute lymphoblastic leukemia (ALL) in Welsh population (Dorak et al. 1999). Since then, there has been no report suggesting the presence of other SNPs within the HFE gene that may directly be associated with childhood ALL. Within the HFE gene, H63D (rs1799945) has been shown to associate with iron overload in the European population (Porto et al., 1998), whereas rs9366637 association is shown in the Asian population (Dorak et al., 2009). It has been speculated that SNPs such as H63D and rs9366637 present in the HFE gene may modify the risk of cancers (Dorak et al., 2006) by virtue of their ability to regulate iron homeostasis. However, a direct association between H63D and rs9366637 and childhood ALL has not been established, other than their potential association with iron overload.
The original observation that C282Y is associated with childhood ALL in Wales and Scotland has not been reproduced and confirmed by others when this particular SNP was evaluated in Mexican and Finnish populations (Ruiz-Argüelles et al., 2006; Hannuksela et al., 2007). This raises the issue of general applicability to use C282Y as a genetic marker for childhood ALL. Failure to replicate a genetic association from one population group to another is common. In the case of C282Y, the underlying basis for the discrepancy is presently unclear. Possible explanations may include differences in population-specific linkage disequilibrium (LD) patterns in the HFE region, or differences in genetic and environmental modifiers among populations.
To the best of the present inventors' knowledge, there are no reliable SNP as a genetic marker to predict the childhood ALL. Yet, there is a continuing need for a genetic marker to predict the probability of childhood ALL. The need for a reliable tagging SNP biomarker for childhood ALL is expected to have utility in the application in child leukemia clinics.